Certain {11 {11 -thiazolinealkanoic acids and esters

ABSTRACT

This invention concerns 2-cycloalkyl or aryl-4-hydroxy-2thiazoline-4 and 5-alkanoic acids which are pharmacologically efficacious as anti-inflammatory agents and which are useful as intermediates in the preparation of the corresponding thiazoles.

United States Patent Robert Anthony Newberry Bourne End, England Apr. 8,1969 Nov. 16, 1971 John Wyeth & Brother Limited Taplow, Maidenhead,Berkshire, England Apr. 9, 1968 Great Britain Appl. No. Filed PatentedAssignee Priority 3,147,273 9/1964 Szmuszkovicz 260/306] PrimaryExaminer--Alex Mazel Assistant Examiner-R. J. Gallagher AttorneyDwightJ. Potter ABSTRACT: This irivention concerns 2-cycloalkyl or aryl-4-hydroxy-2-thiazoline-4 and 5-alkanoic acids which are pharmacologicallyefficacious as anti-inflammatory agents and which are useful asintermediates in the preparation of the corresponding thiazoles.

CERTAIN A-THIAZOLINEALKANOIC ACIDS AND ESTERS This invention relates tonovel nitrogen and sulfur contain ing heterocyclic compounds. Inparticular it concerns 2- cycloalkyl or ary-4-hydroxy-2-thiazoline-4 and-alkanoic acids which in standard pharmacological test procedures withlaboratory animals exhibit usefulness as anti-inflammatory agents. Thecompounds are also useful in the preparation of pharmacologically active2-cycloalkyl-or arylthiazole-4- and 5-alkanoic acids.

The invention provides novel 4-hydroxy-2-thiazoline-4 and S-alkanoicacids and their esters of general formula I H OH RQ L...

wherein R is selected from the group consisting of cycloloweralkyl,phenyl, substituted phenyl such as loweralkylphenyl, loweralkoxyphenyl,halophenyl, nitrophenyl, diloweralkylaminophenyl andtrifluoromethylphenyl, naphthyl and heterocyclyl such as thienyl andfuryl; R is selected from the group consisting of hydrogen and loweralkyl and R is a group selected from lower alkanoic acid residues andtheir lower alkyl esters at the 4- and 5- positions while the group R isat the other of said positions, and acid addition salts thereof.

The terms loweralkyl," loweralkoxy" and the like are meant to includeboth branched and straight chain moieties having from 1 to about 6carbon atoms.

The compounds of general formula l, in the form of a hydrohalide may beprepared by reacting a compound of the general formula II(b) with athioamide of the general formula where R, R and R have the meaningsdefined above and Hal is a halogen atom, under mild conditions. Thetemperatures used for the reaction must be below the dehydrationtemperature of the thiazoline hydrohalide. The optimum temperature willtherefore depend on the particular reactants used and temperatures below50 C. such as room temperature are preferred. It is also preferable tocarry out the reaction in an inert organic solvent in which thethiazoline hydrohalide is insoluble. If R is an aliphatic acid group andif the reaction is carried out in a lower alkanol such as isopropanol inthe presence of a base such as an alkali metal carbonate, the freethiazoline aliphatic acid can be obtained. On the other hand it isgenerally more convenient to use a reactant in which R is a lower alkylester of an aliphatic acid, e.g. the ethyl ester. Conveniently equimolaramounts of the reactants are used and the reaction mixture is heated tothe required temperature or in some cases is merely kept at roomtemperature for a short time or overnight. The thiazolines provided bythe invention can be separated in known manner, e.g. by filtration, andthe filtrate may be acidified to precipitate additional product. Thefree bases of the thiazolines can be prepared from the hydrohalides bytreatment with a base, e.g. with an alkali metal carbonate.

The starting compounds lI employed in the above reaction are eithercommercially available or are readily prepared by organic procedureswell known to the art.

In the preparation of 4-hydroxy-thiazoline-4-acetic acids they-halo-acetoacetic acid is, of course, protected in conventional mannerto prevent decarboxylation and after the cyclization reaction theprotecting group is conventionally removed, for instance using a benzylester which is removed by catalytic hydrogenation.

When the 4-hydroxy-thiazolines of the invention are employed asintermediates to prepare the corresponding thiazoles, they can bedehydrated by heating to above the dehydration temperature, particularlyin the presence of an acid. The 4-hydroxythiazolines of the inventionare readily dehydrated on heating when in the form of a hydroacid salt,the free bases being more stable. Dehydration may be effected byrefluxing the compound in the presence or of an organic solvent in thepresence of a sulfonic acid, eg benzene sulfonic acid or p-toluenesulfonic acid using a water separator until water is no longer evolved,or more simply by heating in an alkanoic acid such as glacial or aqueousacetic acid. When the reaction is complete the thiazole can be recoveredconventionally, for instance the reaction mixture can be evaporated toreduced volume and the product crystallized from a solvent, for instancean alcohol. The thiazoles in general are antiinfiammatory agents whentested on warm-blooded animals such as by the tests of Winter et al. inProc. Soc. Biol. Med. lll, 544 1962) and Buttle et al. in Nature, I79,629 (I957 As the compounds of general formula (I) generally showpharmaceutical activity, for example, anti-inflammatory activity, theinvention provides a pharmaceutical composition comprising a compound ofgeneral formula (I), or an acid addition salt thereof, and apharmaceutically acceptable carrier.

When the compounds of this invention are employed as anti-inflammatoryagents they can be administered to warmblooded animals, e.g. mice, rats,rabbits, dogs, cats, monkeys, etc. alone or as a pharmaceuticalcomposition in combination with pharrnaceutically acceptable carriers.The carrier may be solid, liquid or creamlike and any suitable carrierknown to the art can be used. The composition can be in unit dose form,for example as tablets or capsules or it can be in the form of asolution. The compositions can be administered orally or parenterally byinjection and the composition can, for parenteral administration, be inthe form of a sterile solution or suspension containing other solutes,for example enough saline or glucose to render the solution isotonic.The particular carrier and proportion of carrier to active compound willbe determined by the nature of the compound, the chosen route ofadministration and standard pharmaceutical practice.

The dosage of the thiazoline will vary with the form of administrationand the particular compound chosen. Furthermore, it will vary with theparticular subject under treatment. Generally, treatment is initiatedwith small dosages substantially less than the optimum dose of thecompound. Thereafter, the dosage is increased by small increments untilthe optimum effect under the circumstances is reached. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects. The following examplesillustrate the invention:

EXAMPLE 1 Ethyl 4-hydroxy-2-phenyl-2-thiazolin-4-acetate hydrobromideEthyl 4-bromo-3-oxobutyrate (5 g.) in acetone (10 ml.) is added tothiobenzamide (3.3 g.) in acetone (50 ml.). After 16 hours at roomtemperature, the required hydrobromide salt is filtered off(2.0 g., 24percent) m.p. 77-78 C. Analysis: Found: C, 44.8; H, 4.8; N, 4.0. C,H,,,BrN0 S, requires C, 45.1; H, 4.7; N, 4.0 percent.

In a similar manner, the following thioamides give the hydrobromideproduct indicated, using the above-named ester reactant.

Thioamide Product m-Trifluoromethylthiobenzamide W m p-)Methylthiobenzamide p-Nitrophenylthiothiazoline-4-acetate butyric acidEthyl 4-hydroxy-2-(p-bromophenyl)-2- thiazoline-4-acetate Ethyl4-hydroxy-2-(p-chlorophcnyl)-2- thiazolin-4-acetate4-Acetyl-4-bromobutyric acid thiazolint-acetate Ethyl 4 hydroxy-2-(mtrifluoromethylphenyl)-2-thiap-Methyl-thiobcnzamide-2-phenyl-2-thiazolinc-S-propionic acid 4-Hydroxy-4-methyl -2-(p-tulyl)-2 -thiazoline-S -propionic acid -acetate Ethyl4-hydroxy-2(p-nitrobenzamide phenyl) 2-thiazoline-4 -acetate EXAMPLE 2Ethyl 2-cyclohexyl-4-hydroxy-4-methyl-2-thiazolin-5- acetate requires C,46.1; H, 6.7; N, 3.9 percent.

In a similar manner, the following products indicated:

reactants give the Keto-ester Thioamide Hydroxy-thiazoline Ethylfl-acetyl-flp-Methoxythio- Ethyl 4hydroxy2 bromo-propionate benzamidep-rnethOXyphenyl) Ethyl B-acetyl-flbromopropionate EthylB-acetyl-flbromo-prcpionate Ethyl 4-acetyl-4- bromo-butyrate Ethyl4-acetyl-4- bromo-butyrate Thiophen-2-thio carboxamide Naphthalene-2-thiocarboxamide Thiobenzamide p-Chlorothiobenzainide EXAMPLE 3-4-methyl-2-thiazoline-S-acetate Ethyl 4-hydroxy 4 -methyl-2-(2-thienyl)-2-thiazoline-S-acetate Ethyl 4-hydroxy-4 -methyl-2-(2-naphthyl)-2-thiazoline-S-acetate Ethyl 4-hydroxy-4 -methyl-2-phenyl-2thiaZoIine-S- propionate Ethyl 2 (p-chlorophenyl)-4-hydroxy -4methyl-2-thiazoline-S-propionate2-Cyclohexyl-4-hydroxy-4-methyl-2-thiazolin-5-acetic acid The reactionof cyclohexylthiocarboxamide (7.15 g., 0.05 mol.) andB-acetyl-fl-bromopropionic acid (9.75 g., 0.05 mol.) according to themethod of Example 2 gives 10.16 g. (60.5 percent) of the thiazoline acidas its hydrobromide, m.p.

Analysis: Found: C, 43.1; H, 6.0; N, 4.5C, H NO S.HBr

requires C, 42.8; H, 6.0; N, 4.2 percent.

In a similar manner, the following reactants give the productsindicated:

Keto-acid Thioamide Hydroxy-thiazoline fi-Acetyl-fl-bromopropionic acid4-Acetyl-4-bromop-Dimethylaminothiobenzamide Furan-2-thiocarboxamideThiobenzamide Z-(p-Dimethylaminophenyl)-4- hydroxy-4-methyl-2-thiazoline--acetic acid Z-(Z-Furyl )4-hydroxy-4-methyl-2 -thiazoline-5-acetic acid 4-Hydroxy-4-rnethyl 0 EXAMPLE 4 Ethyl4-hydroxy-2-cyclohexyl-2-thiazolin-4-acetate The reaction ofcyclohexylthiocarboxamide (7.15 g., 0.05 mol.) and ethyl4-bromoacetoacetate (10.41 g., 0.05 mol.) by the method of Example 2affords l 1.0 g. (62.5 percent) of the title compound as itshydrobromide, m.p. l24-l 25 C. Analysis: Found: C, 44.5; H, 6.3; N,4.05. C H No sl-lBr requires C, 44.3; H, 6.3; N, 4.0 percent.

EXAMPLE 5 Ethyl 2-p-chlorophenyl-4-hydroxy-2-thiazoline-4-acetate Asolution of p-chlorothiobenzamide (8.59 g., 0.05 mol.) in acetone (40ml.) is added to a solution of ethyl 4- bromoacetoacetate (10.41 g.,0.05 mol.) in acetone and the mixture is allowed to stand at roomtemperature for 21 hours. The crystalline material after filtering offand washing with ice-cold acetone and ice-cold ether and drying affordsthe title compounds (8.05., 42.3 percent) as its hydrobromide, m.p.97-98 C. Analysis: Found: C, 41.0; H, 3.8; N, 3.5. C, H, ClNO S.HBrrequires C, 41.0; H, 4.0; N, 3.7 percent.

The hydrobromide on treating with sodium hydrogen carbonate gives a 72.8percent yield of the free base, m.p. l09-1 10 C. after recrystallizingfrom ether.

Analysis: Found: C, 52.1; H, 4.6; N, 4.6. C H ClNO S requires C, 52.1;H, 4.7; N, 4.7 percent.

In a similar manner the following reactants give the products indicated:

Keto-ethyl ester Thioamide Hydroxy-thiazoline4-Bromo-acetop-Methoxythio- Ethyl 4-hydroxy-2- acetate benzamide(p-methoxy-phenyl) -2-thiazoline-4-acetate 4-Bromo-acetop-Dimethylamino-Ethyl 4-hydroxy-2- acetate thiobenzamide (p-dimethyl-aminophenyl)-2-thiazoline-4-acetate 4-Bromo-aceto- Thiophene-2- Ethyl4-hydroxy-2 acetate thiucarboxamide (2-thienyl(-2- thiazoline4- acetate4-Btomo-aceto- Furan-2-thio- Ethyl 2-(2furyl) acetate carboxamide-4hydroxy-2thiazoline-4-acetate 4-Bromo-aceto- Naphthaline-Z- Ethyl4-hydroxy-2 acetate \hiocarboxamide (2-naphthyl )-2- thiazoline-4-acetate.

EXAMPLE 6 4-Hydroxy-2-(p-chlorophenyl)-2-thiazolin-4-propionic acid Thereaction of p-chlorothiobenzamide and S-bromo-laevulinic acid by themethod of Example 2 affords the title compound.

EXAMPLE 7 The new and novel compounds of the present invention instandard pharmacological test procedures generally demonstrate anability to reduce inflammation and are useful as agents for thetreatment of inflammation.

ln the pharmacological evaluation of the properties of the compounds ofthis invention, the effects in vivo of the compounds are tested in theprocedure of Winter et al. and Buttle et al. specified above.

The procedure employed is: Anti-inflammatory activity of a test compoundof the invention is assessed by its ability to inhibit experimentallyinduced edema in the hind paw of male Sprague-Dawley rats weighing120-165 grams. The compound is administered orally as a solution orsuspension in physiological saline (plus 1 drop Tween 80) in a volume ofml./kg. at various concentrations. Each compound is given to six ratsand vehicle alone is administered to six other rats as a control. Sixtyminutes after drug administration, edema is induced by an injection of0.05 ml. of a 1 percent carrageenin solution into the subplanter tissueof the rats right hind paw. Paw volume is then immediately measuredvolumetrically with a plethysmograph and again after 3 hours. The meanvolume of swelling for the control group is calculated and compared tothe test groups. Compounds that inhibit swelling approximately percentas compared to controls are active. Inhibition is calculated by theformula:

Percent inhibition mean vol. swelling of test X 100 Mean vol. swellinnzof control Mean vol. swelling of control- The compounds of generalformula I when administered orally in the above test procedure at adosage of 10 to 250 EXAMPLE 8 Elhylz r L. t A L Lactose Magnesiumutcurat Capsules of the above were made up by thoroughly mixing togetherbatches of the above ingredients and filling hard gelatine capsules (250mg.) with the mixture.

EXAMPLE 9 Ethyl 2-p chlorophenyl-4-hydroxy-Zthiazoline-4acetate I25 mg.Lactose I00 mg. Avicel 30 mg. Dried Maize Starch 40 mg. Magnesiumstearate 5 mg.

Tablets of the above composition were made by milling the activeingredient to 40-mesh (British Standard), sieving through a GO-mesh(British Standard) sieve, mixing the milled material with the othercomponents and compressing to form tablets.

What is claimed is:

l. A compound selected from the group consisting of those having thegeneral formula:

. wherein R is seEcted from the group consisting of cyclohexyl,

phenyl, monoloweralkylphenyl, monoloweralkoxy-phenyl, monohalophenyl,mononitrophenyl, mono(diloweralkylamino)-phenyl,-trifluoromethylphenyl,thienyl, furyl and naphthyl; R is a substituent at the 4- or 5- positionand is selected from the group consisting of hydrogen and lower alkyl,and R is a substituent at the other of the said 4- and 5- positions andis a radical of the formula 2)rz wherein n is l or 2 and R is hydrogenor lower alkyl; and their acid addition salts with pharmaceuticallyacceptable acids.

2. A compound according to claim I which is ethyl 4-hydroxy-2-phenyl-2-thiazoline-4-acetate.

3. A compound according to claim 1 which is ethyl 4-hydroxy-2-cyclohexyl-2-thiazoline 4-acetate.

4. A compound according to claim 1 which is ethyl 4-hydroxy-2-(halophenyl)-2-thiazoline-4-acetate.

5. A compound according to claim 1 which is ethyl 4-hydroxy-Z-(trifluoromethylphenyl)-2-thiazoline-4-acetate.

6. A compound according to claim I which is ethyl 4-hydroxy-2-tolyl-2-thiazoline-4-acetate.

7. A compound according to claim 1 which is ethyl 4-hydroxy-Z-nitrophenyl-2-thiazoline-4-acetate.

8. A compound according to claim 1 which is 2halophenyl-4-hydroxy-Z-thiazoline-4-acetic acid.

9. A compound according to claim I which is ethyl 4-hydroxy-Z-(p-methoxyphenyl)-2-thiazoline-4-acetate.

10. A compound according to claim 1 which is2-halophenyl-4-hydroxy-Z-thiazoline-4-propionic acid.

2. A compound according to claim 1 which is etHyl4-hydroxy-2-phenyl-2-thiazoline-4-acetate.
 3. A compound according toclaim 1 which is ethyl 4-hydroxy-2-cyclohexyl-2-thiazoline-4-acetate. 4.A compound according to claim 1 which is ethyl4-hydroxy-2-(halophenyl)-2-thiazoline-4-acetate.
 5. A compound accordingto claim 1 which is ethyl4-hydroxy-2-(trifluoromethylphenyl)-2-thiazoline-4-acetate.
 6. Acompound according to claim 1 which is ethyl4-hydroxy-2-tolyl-2-thiazoline-4-acetate.
 7. A compound according toclaim 1 which is ethyl 4-hydroxy-2-nitrophenyl-2-thiazoline-4-acetate.8. A compound according to claim 1 which is2-halophenyl-4-hydroxy-2-thiazoline-4-acetic acid.
 9. A compoundaccording to claim 1 which is ethyl4-hydroxy-2-(p-methoxyphenyl)-2-thiazoline-4-acetate.
 10. A compoundaccording to claim 1 which is2-halophenyl-4-hydroxy-2-thiazoline-4-propionic acid.